Background: Prevention of early neurological deterioration (END) is becoming an important therapeutic target in acute ischemic stroke management. The aim of the study is to ascertain the causes and predictors of early neurological deterioration following thrombolysis and determine the predictive value of IScore. Methods: In this single center prospective study, we analyzed clinical, imaging and outcome data in 168 patients thrombolyzed intravenously ≤4.5 hours from onset of stroke. Early neurological deterioration was defined as worsening ≥2 points in the NIHSS score at 24 hours. Results: END occurred in 34 patients (20%) and caused significantly worse short term outcome. Ischemic END (ENDi) (n = 23) was twice as common as symptomatic hemorrhage (ENDh) (n = 11). Ischemia progression (n = 15) was the most common cause. Early malignant edema was another major cause. On multivariate analysis, significant predictors (p <.05) were proximal artery occlusion [all END (p <.001), ENDi and ENDh], previous ischemic insults (all END) and raised diastolic blood pressure (ENDh). ENDi was more common in those with carotid artery occlusion, large vessel disease and previous ischemic insults. ENDh was more common in those with raised diastolic blood pressure and NIHSS-ASPECTS mismatch. For patients with NIHSS <14, IScore >105 and for NIHSS ≥14, IScore >175 was associated with higher risk of END. Conclusion: END occurs in one fifth of patients after intravenous thrombolysis; ENDi outnumbers ENDh. Proximal artery occlusion is a major predictor for END. Potentially modifiable risk factors include admission hyperglycemia and elevated blood pressures. Distinct factors characterize ENDh and ENDi and can guide prevention and management strategies. IScore identifies patients at risk for END.